α-Acylureidocephalosporins and salts and esters thereof

ABSTRACT

Compounds which are clinically important cephalosporins and salts and esters thereof having a wide spectrum of activity against Gram-positive bacteria but especially against Gram-negative bacteria such as Pseudomonas spp. against which commercially available cephalosporins are normally inactive. Preferred compounds of the invention are also active against Gram-negative cephalosporinase-producing organisms such as Enterobacter spp., Serratia spp. and indole-positive Proteus; methods of preparation are described.

CROSS REFERENCE

This is a continuation of Ser. No. 478,741 filed June 12, 1974, and nowabandoned.

This invention relates to cephalosporins which have, in general, a broadspectrum of antibacterial activity, being active against many species ofGram-positive and Gram-negative bacteria. They are, therefore, useful astherapeutic (and, to a lesser extent, prophylactic) agents in animals,including man and poultry. The invention further relates to methods forthe preparation of these cephalosporins and to their use in therapy.

Although there are now available a number of semi-syntheticcephalosporins having what is known as broad spectrum activity, nosingle cephalosporin is yet available which has a clinically usefullevel of antibacterial activity against all the pathogenic organismsencountered in clinical practice The search thus continues forbroad-spectrum cephalosporins which have advantages, either in improvedantibacterial effectiveness or wider spectrum of activity over theavailable cephalosporins.

According to the present invention there is provided a cephalosporin offormula (I) or a pharmaceutically acceptable salt or ester thereof:##STR1## wherein Y is oxygen or sulphur, R¹ is an organic radicalcontaining up to 20 carbon atoms; R² is alkyl having from 1 to 3 carbonatoms, or benzyl; or R¹ and R² together with the carbon and nitrogenatoms to which they are attached form a 5,6 or 7 membered ring; R³ isphenyl, phenyl substituted by one or more functional groups selectedfrom hydroxy, halogen, nitro, alkoxy containing from 1 to 3 carbonatoms, and amino groups, 2- or 3-thienyl, cycloalkyl having from 3 to 7carbon atoms or alkyl having from 1 to 4 carbon atoms; R⁴ is acetoxy oris a carbon, nitrogen or a sulphur nucleophile. Preferably Y is oxygen.

The group R¹ may for example be C₁₋₁₀ alkyl; C₁₋₁₀ alkenyl; aralkyl oraralkenyl in which the alkyl and alkenyl radicals are C₁₋₁₀ and the arylradicals are phenyl, thienyl, furyl, pyridyl or substituted phenylwherein the substituents are selected from C₁₋₁₃ alkyl, C₁₋₃ alkoxy,halogen, nitro and amino groups; C₁₋₁₀ alkoxy, C₅₋₇ cycloalkoxy; C₁₋₁₀alkylamino; phenyl; furyl; thienyl; pyridyl; substituted phenyl whereinthe substituents are selected from C₁₋₃ alkyl, C₁₋₃ alkoxy, halogen,nitro and amino groups; functionally substituted C₁₋₁₀ alkyl wherein thefunctional substituent is, for example, C₁₋₃ alkylthio, C₁₋₃ alkoxy orphenoxy.

Specifically, the group R¹ may be, for example, methyl, ethyl, n- oriso-propyl, n-; sec- or tert-butyl, n-pentyl, n-hexyl, n-heptyl,ω-methylheptyl, n-octyl, ω,ω-dimethyloctyl, prop-2-enyl,3-methylprop-2-enyl, 1-methyl-prop-2-enyl, but-2-enyl, oct-2-enyl,2-phenylethyl, 2-phenylethenyl, 2-(2¹ -methoxyphenyl)ethenyl, 2-(4¹-nitrophenyl)ethen-yl,2-(3¹,4¹,5¹ -trimethoxyphenyl)ethenyl, 2-(fur-2¹-yl)enyl. 3-phenylpropyl, 1-methyl-2-phenylethenyl, 4-phenylbut-2-enyl,5-phenylpent-2-enyl, 1-methyl-5-phenylpent-2-enyl, methoxy, ethoxy, n-or sec-propoxy, n-, sec- or tert-butoxy, n-pentoxy, n-hexyloxy,cyclohexyloxy, methylamino, dimethylamino, phenyl, 2-methoxyphenyl,2-chlorophenyl, 2-methoxy phenyl, 3,4,5-tri-methoxyphenyl,4-nitrophenyl, 2-methylphenyl, 4-methylphenyl, methoxymethyl,ethoxymethyl, methylthiomethyl, phenoxymethyl.

The group R² may be, for example, methyl, ethyl or benzyl. Preferably R²is methyl.

When R² and R¹ are taken together with the carbon and nitrogen atoms towhich they are joined, the ring which is formed may be, for example, oneof the following: ##STR2## in which n is an integer from 3 to 5 and m isan integer from 2 to 4 and R_(a) is hydrogen, C₁₋₃ alkyl, C₁₋₃ acyl orC₁₋₃ alkylsulphonyl. Preferably the ring formed isimidazolidin-2-on-1-yl, 3-acetylimidazoldin-2-on-1-yl,3-methylsulphonyl-imidazolidin-2-on-1-yl or hexahydroazepin-2-on-1-yl.

The group R³ may be, for example, phenyl, 4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 4-nitrophenyl, 4-aminophenyl, 2-thienyl,3-thienyl, cyclopropyl, cyclohexyl, cyclohexa-1,4-dienyl, iso -propyl ormethyl group. Preferably R³ is phenyl, 4-hydroxyphenyl,3-chloro-4-hydroxyphenyl or 3-thienyl.

The group R⁴ may be inter alia a strong carbon, nitrogen or sulphurnucleophile. Such nucleophiles displace the acetoxy group from thenucleus of 7-aminocephalosporanic acid and such displacement has beenobserved with various pyridines (Hale et.al. Biochem J. 79, 403, (1961)and Spencer et.al., J.Org. Chem (U.S.A.) 32 500, (1967)); other aromaticheterocycles (Hale et.al loc.cit;) Kariyone et al J. Antibiotics, 23,131 (1970); and Spencer et.al. loc. cit.); Xanthates anddithiocarbromates Van Heyningen et.al. J.Chem.Soc. (London) 5015 (1965))and anilines Bradshaw et.al. J.Chem.Soc. (London) 801 (1968)). Examplesof particular R⁴ groups include the following: ##STR3## Preferably R⁴ is2-methyl-1,3,4-thiadiazolyl-5-thio,1-methyl-(1H)-1,2,3-tetrazolyl-5-thio, 2-methyl-1,3,4-oxadiazolyl-5-thioor (1H)-1,2,4-triazolyl-5-thio.

Preferably the configuration of the carbon atom to which the group R³ isattached is D.

Suitable pharmaceutically acceptable salts include the sodium,potassium, calcium, magnesium or aluminium salts and ammonium orsubstituted ammonium salts, e.g. those with trialkylamines such astriethylamine, procaine, dibenzylamine and triethanolamine.

In the case of compounds (I) which contain a basic nitrogen site in theside chain, acid addition salts may also be formed. Such salts include,for example, inorganic salts such as the sulphate, nitrate, phosphate,borate and hydrohalides e.g. hydrochloride, hydrobromide andhydroiodide, and organic salts such as the acetate, oxalate, tartrate,malate, citrate, succinate, benzoate, ascorbate and methanesulphonate.

Suitable pharmaceutically acceptable esters include especially thosewhich break down readily in the human body to leave the parent acid e.g.acyloxyalkyl esters such as acetoxymethyl, pivaloyloxymethyl,α-acetoxyethyl, α-acetoxybenzyl and α-pivaloyloxymethyl, andalkoxycarbonylalkyl esters such as methoxycarbonyloxymethyl orα-methoxycarbonyloxyethyl esters. Other suitable esters of the readilyhydrolysable type include lactone, thiolactone and dithiolactone esters(i.e. compounds of formula (I) wherein the 4-carboxy group is esterifiedas ##STR4## wherein X¹ and Y¹ are oxygen or sulphur and Z¹ is a divalentradical) especially the phthalide and substituted phthalide esters e.g.5,6-dimethoxyphthalide esters.

The compounds of formula (I), it will be noted, fall into two structuralclasses, namely those wherein the group R¹ is joined to the carbonylgroup via a C--C bond and those wherein it is joined via an N--C bond.

The compounds of this invention may be prepared by reacting a compoundof formula (II) or a salt, ester or silyl derivative thereof: ##STR5##wherein the dotted line represents a bond in the 2- or 3-position, n is0 or 1 and R⁴ is as defined with respect to formula (I) with a reactiveN-acylating derivative of an acid of formula (III): ##STR6## wherein Y,R¹, R² and R³ are as defined in formula (I) and wherein any reactiongroups, such as amino and hydroxy groups may be blocked, and thereafter,if necessary carrying out one or more of the following steps:

(i) converting a Δ² isomer into the desired Δ³ isomer (ii) removal ofany silyl groups by alcoholysis or hydrolysis (iii) reduction of asulphoxide compound to form the desired sulphide compound (iv) removalof any blocking groups in the acyl side chain R (v) conversion of anester compound to a free acid compound or salt thereof.

By the term "silyl derivative" of compound (II) we mean the product ofthe reaction between compound (II) and a silylating agent such as ahalodialkylsilane, a halotrialkylsilane, a halodialkoxysilane or ahalotrialkoxysilane, or a corresponding aryl or aralkylsilane andcompounds such as hexamethyldisilazane. The silyl derivatives ofcompound (II) are extremely sensitive to moisture and hydroxyliccompounds, and, after, reaction with the N-acylating derivatives of theacid (II), the silyl groups of the intermediate acylated compound can beremoved by alcoholysis or hydrolysis.

A reactive N-acylating derivative of the acid (II) is employed in theabove process. The choice of reactive derivative will of course beinfluenced by the chemical nature of the substituents in the acid. Thus,when the acid contains only acid stable groups, an acid halide is asuitable N-acylating derivative, preferably the acid chloride.

Such reagents, would however, be avoided when an acid labile group waspresent in the acid (III). In such cases a suitable N-acylatingderivative is a mixed anhydride. For this purpose particularlyconvenient mixed anhydrides are the alkoxyformic anhydrides.

Alternative N-acylating derivatives of acid (III), are activated esters.Such activated esters, for example the ester formed with1-hydroxybenzotriazole or N-hydroxysuccinimide, may be prepared in situby the reaction of the acid with the appropriate hydroxy compound in thepresence of a carbodiimide, preferably dicyclohexylcarbodiimide.

Other reactive N-acylating derivatives of the acid (II) include thereactive intermediate formed by reaction in situ with a carbodiimide orcarbonyldiimidazole, but the literature on the preparation ofsemi-synthetic penicillins contains examples of other reactiveN-acylating derivatives of acids suitable for coupling to 6-APA.

It will be understood, of course, that where a free acid of type (I) ora salt thereof is desired, it may be convenient to carry out theacylation reaction using an ester of (II), and then to remove the estergroup. Vice versa, if an ester is required, it may be convenient tocarry out the acylation reaction using 7-ACA or a salt thereof andthereafter to esterify the free acid.

In the above process, if it is necessary to block any reactivesubstituents in the acid (III), conventional chemical blocking groupsare known. Thus, if desired, any free amino groups may be blocked byconversion to t-butyloxycarbonyl or benzyloxycarbonylamino groups, orthe amino group may be blocked as the nitro group which is laterconverted to the amino group.

When the compound resulting after N-acylation contains a sulphoxidegroup at the 1-position of the cephem ring this may be reduced byconventional methods, for example, those described in British Pat. No.1,280,693. One such method is treatment with triphenylphosphine andacetyl chloride. When the resultant compound is a Δ² cephem, the desiredΔ³ cephem may be obtained by treatment of the former with a base, e.g.an alkali metal hydroxide or tertiary amine bases such as pyridine andtriethylamine, or by oxidation to the Δ² cephem sulphoxide followed byreduction to the Δ³ cephem. Methods for converting an ester compound toa free acid or base will depend on the particular ester in question, forexample acid--or base--hydrolysis as well as enzymically catalysedhyrolysis may be used. However, to minimise isomerisation and sidereactions aqueous solvents are better avoided and Lewis acids arepreferable as means for de-esterification in appropriate cases.

Another method for the preparation of compound (I) is to react acompound of formula (IV) or a salt ester or silyl derivative thereof:##STR7## wherein the dotted line represents a bond in the 2- or3-position, R³ and R⁴ are as defined with respect to formula (I), with acompound of formula (V) ##STR8## wherein Y, R¹, R² and R³ are as definedwith respect to formula (I), and, thereafter, if necessary, carrying outone or more of the following steps:

(i) converting a Δ² isomer into the desired Δ³ isomer (ii) removal ofany silyl groups by alcoholysis or hydrolysis (iii) reduction of asulphoxide compound to form the desired sulphide compound (iv) removalof any blocking groups in the acyl side chain R (v) conversion of anester compound to a free acid compound or salt thereof.

The compounds of this invention wherein R⁴ is a carbon, sulphur ornitrogen nucleophile, may also be prepared from the correspondingcompound wherein R⁴ is acetoxy, by nucleophilic displacement of theacetoxy group. In such a process, a compound of formula (VI) or a salt,ester or silyl derivative thereof: ##STR9## wherein the dotted linerepresents a bond in the 2- or 3-position, n is 0 or 1, Y, R¹, R², andR³ are as defined in formula (I), and wherein any reactive groups may beblocked, is reacted with the appropriate carbon, nitrogen or sulphurnucleophile and thereafter, if necessary, one or more of the followingsteps is carried out:

(i) converting a Δ² isomer into the desired Δ³ isomer (ii) removal ofany silyl groups by alcoholysis or hydrolysis (iii) reduction of asulphoxide compound to form the desired sulphide compound (iv) removalor any blocking groups in the acyl side chain R (v) conversion of anester compound to a free acid compound or salt thereof.

The compounds of this invention are broad spectrum cephalosporins, i.e.cephalosporins which not only have activity against Gram-positivebacteria, but also against a number of clinically importantGram-negative organisms. The preferred compounds of this invention areactive against such important organisms as Pseudomonas spp. againstwhich the commercially available cephelosporins are normally inactive.In addition the preferred compounds are active against a number ofGram-negative cephalosporinase producing organisms e.g. Enterobacterspp. Serratia spp, indole-positive Proteus.

The following Examples illustrate the preparation of some of thecompounds of this invention.

EXAMPLE 1 Preparation of SodiumD-α-(N-imidazolidin-2-onylecarbonylamino) benzyl cephalosporin

D-α-amino benzyl cephalosporin dihydrate (2.2 g) was dissolved in water(30 ml), acetone (5 ml) and triethylamine (0.7 ml). A solution ofimidazolidin-2-onyl carbonyl chloride (0.75 g) in dry acetone (20 ml)was slowly added together with a further equivalent of triethylamine(0.7 ml) at such a rate to hold the pH of the reaction mixture atbetween 7.5 and 8.0. After the addition was complete, (about 5 minutes),the mixture was stirred for 1 hour with little further change in pH. Theacetone was then removed under reduced pressure, the aqueous concentratecovered with ethyl acetate (35 ml) and the two phases chilled to 0° C.The pH was carefully adjusted to 1.5 with dilute hydrochloric acid withvigorous stirring. The phases were separated and the aqueous phasequickly re-extracted with fresh ethyl acetate (15 ml). The combinedorganic phases were washed with water (20 ml) and then with saturatedbrine solution (2×50 ml). The organic phase was then filtered through asiliconised filter paper to remove the final traces of brine solutionand then treated with 1.0 N sodium 2-ethylhexoate/isopropanol (5 ml)with stirring. The pale yellow precipitate was filtered, thoroughlywashed with dry diethyl ether and finally dried in vacuo to give therequired cephalosporin, [(1.2 g), i.r. νmax. (nujol) 1768 cm⁻¹ (β-lactamCO)]. This material gave an iodometric assay of 54%, and when subjectedto paper chromatography in butanol-ethanol-water, had an R_(f) 0.23,whereas the starting material, cephaloglycin, exhibited an R_(f) of0.19.

EXAMPLE 2 Preparation of Sodium D-α-(N-3-cinnamoyl-3-methyl ureido)benzyl cephalosporin

A solution of D-α-aminobenzyl cephalosporin (2.2 g) in water (30 ml),acetone (5 ml) and triethylamine (0.7 ml) was treated withN-chloroformyl-N-methyl cinnamide (1.12 g) in dry acetone (25 ml),simultaneously with a further equivalent of triethylamine (0.7 ml), suchthat the pH of the reaction mixture was maintained at 7.5 to 8.0. Uponcompletion of the addition, (about 5-8 minutes), the reaction mixturewas stirred for 1 hour further when the acetone was removed by twothorough diethylether (2×100 ml) extractions. The pale yellow aqueousphase was covered with ethyl acetate (40 ml), chilled to 0° C. andcarefully acidified to 1.5 with dilute hydrochloric acid withcontinuous, vigorous stirring. The phases were separated, the aqueousphase re-extracted with fresh ethyl acetate (20 ml). The combinedorganic phases were washed with water (20 ml) followed by saturatedbrine solution (2×50 ml). The last traces of brine were removed byfiltration through a silicone-filter paper and then treated with 1.0 Nsodium 2-ethyl hexoate/isopropanol (5 ml) with stirring. The thick whiteprecipitate was filtered, well washed with dry diethyl ethyl and finallydried in vacuo to yield the desired material [(2.8 g) i.r. νmax. (nujol)1770 cm⁻¹ (β-lactam CO)]. When subjected to paper chromatography(butanol-ethanol-water), the product exhibited an R_(f) of 0.51 and gavean iodometric assay of 58%.

EXAMPLE 3 Sodium D-α-(3-Ethoxycarbonyl-3-methylureido)benzylcephalosporin

D-α-Aminobenzylcephalosporin dihydrate (2.2 g.) and triethylamine (1.5ml.) in anhydrous dichloromethane (30 ml.) were stirred with molecularsieves, type 4A (2.0 g.), for two hours. The mixture was filtered,cooled in an ice bath and treated with ethyl N-chloroformylN-methylcarbonate (0.84 g.) in dichloromethane (15 ml.). The solutionwas stirred at room temperature for two hours and evaporated to drynessin vacuo. The residue was dissolved in water (100 ml.) washed withethylacetate (2×50 ml.) covered with ethylacetate (50 ml.) and acidifiedto pH 1.5 with N hydrochloric acid then filtered to remove insolublematerial. The ethyl acetate was separated and the aqueous layerreextracted with water (2×50 ml) and saturated brine (50 ml.) dried overanhydrous magnesium sulphate, diluted with anhydrous ether (100 ml). andtreated with 2 N sodium 2-ethylhexoate in methyl isobutylketone untilprecipitation ceased. The cephalosporin sodium salt was collected,washed with anhydrous ether and dried in vacuo over phosphoruspentoxide. Yield 1.25 g., 43.1%, n.m.r. spectrum [(CD₃)₂ SO+D₂ O].δ=7.55 (5H, s, aromatic protons). 5.9-5.6 (2H, m, α- and C₇ protons),5.3-4.7 (3H, m, C₆ proton and --CH₂ OCOCH₃), 4.38 [2H, q (J=7H_(z)),NCO₂ CH₂ CH₃ ], 2.13 (3H, S, --OCOCH₃), 1.41 [3H, t(J=7H_(z)) --CO₂ CH₂CH₃ ] . Paper chromatography in butanol-ethanol- water showed a singlezone, R_(f) =0.49.

EXAMPLE 4 Sodium D-α(3-Cyclohexyloxycarbonyl-3-methylureido)benzylcephalosporin

D-α-Aminobenzylcephalosporin dihydrate (2.2 g.) and cyclohexylN-chloroformyl N-methylcarbonate (1.1 g.) were reacted together usingthe method described in example 3 to give the cephalosporin sodium salt,1.01 g. 32%. N.m.r. spectrum [(CD₃)₂ SO+D₂ O], δ=7.40 (5H, s, aromaticprotons), 5.8-5.4 (2H, m, C₇ and α-protons), 5.3-4.5 (4H, m, C₆ proton,--CH₂ OCOCH₃ and cyclohexylmethine proton), 3.5-3.0 (2H, m, C₂ protons),3.10 (3H, s, >N--CH₃), 2.01 (3H, s, --OCOCH₃), 3.1-1.2 (10H, m,cyclohexylmethlene protons). Paper chromatography inbutanol-ethanol-water showed one spot, R_(f) =0.60.

EXAMPLE 5 Sodium D-α(2,4-dimethylallophanamido)benzyl cephalosporin

Anhydrous triethylammonium D-α-aminobenzyl cephalosporinate (0.005 M) indichloromethane (30 ml.) [prepared from the dihydrate of D-α-aminobenzylcephalosporin (2.2 g.) as in example 3] was cooled in an ice bath andthen 2,4-dimethylallophanoyl chloride (0.75 g.) in dichloromethane (15ml.) was added. The solution was stirred at R.T. for two hours thenevaporated to dryness in vacuo. The residue was dissolved in water (100ml.), washed with ethyl acetate (2×50 ml.), covered with fresh ethylacetate (50 ml.) and acidified to pH 1.5 with 1 N hydrochloric acid. Themixture was filtered to remove the insoluble material, the ethylacetateseparated and the aqueous layer extracted with ethyl acetate (50 ml.).The combined ethyl acetate solutions were washed with water (2×50ml.)and saturated brine (50 ml.) then dried over anhydrous magnesiumsulphate. After the magnesium sulphate had been filtered off, the ethylacetate solution was reduced to ca. 25 ml. in vacuo and 2 N sodium2-ethylhexoate in methyl isobutyl ketone (1.5 ml.) added. Theprecipitated sodium salt was collected and washed with anhydrous etherthen dried in vacuo over phosphorus pentoxide. Yield 1.29 g., 49.2%;n.m.r. spectrum [(CD₃)₂ SO+D₂ O], δ=7.38 (5H,s, aromatic protons),5.9-5.3 (2H, m, C₇ and α-protons), 5.2-4.6 (4H,m, C₆ proton and --CH₂OCOCH₃), 3.5-2.9 (2H,m, C₂ methylene protons), 3.13 (3H,s, >N--CH₃),2.73 (3H,s, --NHCH₃), 2.01 (3H,s, --OCOCH₃); u.v. spectrum (95%ethanol), λ_(max) 261.5 nm (ε=7,276). Paper chromatography inn-butanol-ethanol-water showed a single zone, R_(f) =0.41.

The following Example 6-17 were prepared by the method described inExample 5.

EXAMPLE 6 Sodium D-α-(hexahydroazepin-2-one-1-ylcarbonylamino)benzylcephalosporin

From 1-chlorocarbonylhexahydroazepin-2-one and D-α-aminobenzylcephalosporin dihydrate in 40.3% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂O], δ=7.44 (5H,s, aromatic protons), 5.7-5.5 (2H,m, α-proton and C₇proton), 5.2-4.6 (4H,m, C₆ proton and --CH₂ OCOCH₃), 4.1-3.8 (2H,m,hexahydroazepinone C₃ methylene), 3.5-2.1 (2H,m, C₂ methylene), 3.0-2.6(2H,m, hexahydroazepinone C₇ methylene), 2.01 (3H,s, --OCOCH₃), 1.9-1.4(6H,m, hexahydroazepinone C₄, C₅ and C₆ methylene protons); u.v.spectrum (95% ethanol), λ_(max) 263.5 nm (ε=6,509). Paper chromatographyshowed one zone R_(f) =0.58.

EXAMPLE 7 Sodium D-α-(3-cinnamoyl-3-methylureido)benzyl cephalosporinate

From N-chlorocarbonyl-N-methylcinnamamide and D-α-aminobenzylcephalosporin dihydrate in 37.5% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂O], δ=8.0-7.1 (12H,m, aromatic and definic protons), 5.8-5.5 (2H,m, C₇and α-protons), 5.3-4.6 (3H,m, C₆ and --CH₂ OCO-- protons), 3.35 (5H,singlet covering a multiplet, C₂ methylene and >N--CH₃), 2.04 (3H,s,--OCOCH₃); u.v. spectrum (95% ethanol), λ_(max) 279 nm (ε=18,326). Paperchromatography showed a zone at R_(f) =0.52.

EXAMPLE 8 Sodium D-α-(3-crotonoyl-3-methylureido)benzyl cephalosporin

From N-chlorocarbonyl-N-methylcrotonamide and D-α-amiobenzylcephalosporin dihydrate in 24% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂ O],δ=1.89 (3H,m, =CHCH₃), 2.02 (3H,s, --OCO--CH₃), 3.23 (3H, singletcovering a multiplet, >N--CH₃ and C₂ methylene protons), 4.85-4.95(3H,m, C₆ and --CH₂ --OCOCH₃), 5.5-5.7 (2H,m, C₇ and α-protons), 6.7-7.5(2H,m, olefinic protons), 7.40 (5H,s, aromatic protons); u.v. spectrum(95% ethanol), λ_(max) 265 nm (ε=8,684). Paper chromatography showed azone at R_(f) =0.48.

EXAMPLE 9 Sodium D-α-(3-methyl-3-phenylpropionoylureido)benzylcephalosporin

From N-chlorocarbonyl-N-methylphenylpropionamide and D-α-aminobenzylcephalosporin dihydrate in 55.5% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂O], δ=1.03 (3H,s, --OCOCH₃), 2.8-3.5 (9H,m, <N--CH₃, --OCH₂ CH₂ -- andC₂ methylene protons), 4.8-5.0 (3H,m, C₆ proton and --CH₂ OCO--),5.5-5.7 (2H,m, C₇ and α-protons), 7.30 (5H,s, aromatic protons), 7.40(5H,s, aromatic protons); u.v. spectrum (95% ethanol), λ_(max) 264 nm(ε=7,300). Paper chromatography showed a zone at R_(f) =0.63.

EXAMPLE 10 Sodium D-α-[3-methyl-3-(o-methoxycinnamoyl)ureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-o-methoxycinnamamide and D-α-aminobenzylcephalosporin dihydrate in 34.3% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂O], δ=2.03 (3H,s, --OCOCH₃), 3.36 (3H,s, --OCH₃), 3.75 (5H, singletcovering a multiplet, >N--CH₃ and C₂ methylene), 4.85-5.05 (3H,m, C₆proton and --CH₂ OCO--), 5.60-5.80 (2H,m, C₇ and α-protons), 7.0-8.2(11H,m, olefinic and aromatic protons; u.v. spectrum (95% ethanol),λ_(max) 229 (ε=17,856), 277 (ε=17,767) and 331 nm (ε=11,249). Paperchromatography showed a zone at R_(f) =0.38.

EXAMPLE 11 Sodium D-α-[3-methyl-3-(2'-thienyl)acryloylureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-(2-thienyl)acrylamide and D-α-aminobenzylcephalosporin dihydrate in 26.3% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂O], δ=2.03 (3H,s, --OCOCH₃), 3.32 (5,m, >N--CH₃ and C₂ methyleneprotons), 4.7-5.1 (2H,m, C₆ proton and --CH₂ OCO--), 5.5-5.8 (2H,m, C₇and α-protons), 6.8-8.1 (10H,m, olefinic and aromatic protons); u.v.spetrum (95% ethanol), λ_(max) 267 (ε=12,843) and 322.5 nm (ε=15,205).Paper chromatography showed a zone at R_(f) =0.63.

EXAMPLE 12 Sodium D-α-[3-methyl-3-(p-nitrocinnamoyl)ureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-p-nitrocinnamamide and D-α-aminobenzylcephalosporin dihydrate in 13% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂ O],δ=1.97 (3H,s, --OCOCH₃), 2.74 (5H,m, >N-CH₃ and C₂ methylene protons),4.7-5.2 (3H,m, --CH₂ OCO-- and C₆ proton), 5.5-6.0 (2H,m, C₇ andα-protons), 7.0-8.3 (11H,m, aromatic and olefinic protons); u.v.spectrum (95% ethanol), λ_(max) 266 nm (ε=13,797). Paper chromatographyshowed a zone at R_(f) =0.57.

EXAMPLE 13 Sodium D-α-[3-methyl-3-(α-methylcinnamoyl)ureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-α-methylcinnamamide and D-α-aminobenzylcephalosporin dihydrate in 33.5% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂O], δ=2.03 (3H,s, --OCOCH₃), 2.10 (3H,d, CH₃ --CH═), 3.23 (3H,s,>N--CH₃), 3.2-3.5 (2H,m, C₂ methylene), 4.8-5.0 (3H,m, --CH₂ OCO-- andC₆ proton), 5.5-5.7 (2H,m, C₇ and α-protons), 6.80 (1H,m, >C═CH--),7.3-8.1 (10H,m, aromatic protons); u.v. spectrum λ_(max) 266nm(ε=13,797). Paper chromatography showed a zone at R_(f) =0.67.

EXAMPLE 14 Sodium D-α-(3-benzyl-3-cinnamoylureido)benzyl cephalosporin

From N-chlorocarbonyl-N-benzylcinnamamide and D-α-aminobenzylcephalosporin dihydrate in 49.5% yield; n.m.r. [(CD₃)₂ SO+D₂ O], δ=2.03(3H,s, CH₃ OCO--), 3.33 (2H,m, C₂ methylene protons), 4.95 (3H,m, --CH₂OCO-- and C₆ proton), 5.28 (2H,m, PhCH₂ --), 5.67 (1H,d, C₇ proton),5.72 (1H,s, α-proton), 7.40 (17H,m, aromatic and olefinic protons); u.v.spectrum (95% ethanol), λ_(max) 289 nm (ε=14,100). Paper chromatographyshowed a zone at R_(f) =0.64.

EXAMPLE 15 SodiumD-α-[3-(3',4',5'-trimethoxybenzoyl)3-methylureido]benzyl cephalosporin

From N-chlorocarbonyl-N-methyl-3,4,5-trimethoxybenzamide andD-α-aminobenzyl cephalosporin dihydrate in 27% yield; n.m.r. [(CD₃)₂SO+D₂ O], δ=2.03 (3H,s, CH₃ OCO--), 3.17 (5H,m, >N--CH₃ and C₂methylene), 3.83 (9H,m, 3×CH₃ O--), 4.96 (3H,m, --CH₂ OCO-- and C₆proton), 5.63 (1H,d, C₇ proton), 5.68 (1H,s, α-proton), 6.88 (2H,s,trisubstituted phenyl protons), 7.40 (5H,s, Ph--); u.v. spectrum (95%ethanol), λ_(max) 265 nm (ε=11,832). Paper chromatography showed a zoneat R_(f) =0.42.

EXAMPLE 16 Sodium D-α-[3-(ββ-dimethylacryloyl)-3-methylureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-ββ-dimethylacrylamide and D-α-aminobenzylcephalosporin dihydrate in 24.7% yield; n.m.r. spectrum [(CD₃)₂ SO+D₂O], δ=1.9-2.1 ##STR10## 3.20 (2H, s, >N--CH₃), 3.2-3.4 (2H,m, C₂methylene), 4.8-5.0 (3H,m, --CH₂ OCO-- and C₆ proton), 5.6-5.8 (2H,m, C₇and α-protons), 6.20 (1H,m, --CH═C<), 7.42 (5H,s, aromatic protons);u.v. spectrum (95% ethanol), λ_(max) 227 nm (ε=18.460). Paperchromatography showed a zone at R_(f) =0.62

EXAMPLE 17 SodiumD-α-[3-methyl-3-(3',4',5'-trimethoxycinnamoyl)ureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-3,4,5-trimethoxycinnamamide andD-α-aminobenzyl cephalosporin dihydrate in 33.5% yield; n.m.r. spectrum[(CD₃)₂ SO+D₂ O], δ=2.03 (3H,s, --OCOCH₃), 3.2-3.5 (2H,m, C₂ methylene),3.36 (3H,s, >N--CH₃), 3.77 (3H,s, --OCH₃), 3.87 (3H,s, --OCH₃), 3.96(3H,s, --OCH₃), 4.8-5.0 (3H,m, C₆ and --CH₂ OCO--), 5.5-5.7 (2H,m, α-andC₇ protons), 7.1-7.7 )9H,m, aromatic and olefinic protons); u.v.spectrum (95% ethanol), λ_(max) 235.5 (ε=21,396) and 320 nm (ε=17,935).Paper chromatography showed a zone at R_(f) =0.63.

EXAMPLE 18 Sodium D-α-(2-imidazolidonecarbonylamino)benzyl cephalosporin

D-α-(2l -Imidazolidonecarbonylamino)phenylacetic acid (1.32 g., 0.005 M)in anhydrous tetrahydrofuran (20 ml.) was cooled to <-10° and treatedwith N-methylmorpholine (1 drop), triethylamine (0.71 ml.) and ethylchloroformate (0.48 ml.). The resulting suspension was stirred at <-10°for 15 mins. then an ice cooled solution of 7-aminocephalosporanic acid(1.36 g., 0.005 M) and triethylamine (0.71 ml.) in 50% aqueoustetrahydrofuran (30 ml.) was added. The solution was stirred at R.T. forthree hours, tetrahydrofuran was then removed in vacuo and the residuedissolved in water (100 ml.) This aqueous solution was washed with ethylacetate (2×50 ml.) and acidified to pH 1.5 with 1 N hydrochloric acid.The precipitate was collected and dried in vacuo, yield 0.87 g., thensuspended in water (10 ml.) and 0.95 equivalents of 1 N sodiumbicarbonate solution added. The solution was filtered and the filtrateevaporated to dryness in vacuo. Yield 0.70 g., 26%; n.m.r. [(CD₃)₂ SO+D₂O], δ=9.17 [1H, d(J=8 Hz), --NH--], 7.41 (5H,s, aromatic protons),5.9-5.4 (2H,m, C₇ and α-protons), 5.3-4.6 (3H,m, C₆ and --CH₂ OCO--protons), 4.1-3.1 (6H,m, C₂ methylene and imidazolidone methylenes),2.01 (3H,s, --OCOCH₃); u.v. spectrum (95% ethanol) λ_(max) 264 nm(ε=6,527). Paper chromatography in n-butanol, ethanol, water showed onezone, R_(f) =0.32.

EXAMPLE 19 Sodium D-α-(3-cinnamoyl-3-methylureido)benzyl cephalosporin

D-α-(3-Cinnamoyl-3-methylureido)phenylacetic acid (1.69 g., 0.005 M) inanhydrous acetone (15 ml.), was cooled to <-10° then N-methylmorpholine(1 drop), triethylamine (0.71 ml.) and ethyl chloroformate (0.48 ml.)were added. The resulting suspension was stirred at <-5° for 15 minutesthen 7-aminocephalosporanic acid (1.36 g., 0.005 M) and triethylamine(0.71 ml.) in 50% aqueous acetone (30 ml.) pre-cooled to 0°, were added.The solution was stirred at R.T. for three hours, the acetone wasremoved in vacuo and the residue diluted with water (ca. 50 ml.). Thisaqueous solution was washed with ethyl acetate (2×50 ml.), covered withethyl acetate (50 ml.), acidified to pH 1.5 with N-hydrochloric acid,the layers separated and the aqueous layer extracted with ethyl acetate(50 ml.). The combined organic solutions were washed with water (2×50ml.) and brine (50 ml.) then dried over anhydrous magnesium sulphate,concentrate in vacuo and treated with 2 N sodium 2-ethylhexoate inmethyl isobutyl ketone (1.5 ml.). The precipitated solid was collected,washed with anhydrous ether and dried in vacuo. Yield 0.70 g., 22.8%;n.m.r. [(CD₃)₂ SO+D₂ O], δ=8.0-7.1 (12H,m, aromatic and olefinicprotons), 5.8-5.4 (2H,m, C₇ and α-protons), 5.2-4.7 (3H,m, C₆ and --CH₂OCO-- protons), 3.34 (5H, singlet covering a multiplet, >N--CH₃ and C₂methylene), 2.05 (3H,s, --OCOCH₃); u.v. spectrum (95% ethanol), λ_(max)275 nm (ε=17,119). Paper chromatography showed a single zone, R_(f)=0.52.

EXAMPLE 20 Sodium D-α-(3-furylacryloyl-3-methylureido)benzylcephalosporin

From D-α-(3-furylacryloyl-3-methylurieo)phenyl acetic acid and7-aminocephalosporanic acid as in example 21 in 14% yield; n.m.r.spectrum [(CD₃)₂ SO+D₂ O], δ=2.03 (3H,s, --OCOCH₃), 3.32 (5H, singletcovering a multiplet, >N--CH₃ and C₂ methylene protons), 4.8-5.1 (3H,m,--CH₂ OCO-- and C₆ proton), 5.5-5.8 (2H,m, C₇ and α-protons), 6.6-7.9(10H,m, furyl, olefinic and aromatic protons). Paper chromatographyshowed a zone at R_(f) =0.58.

EXAMPLE 21 Sodium D-α-(3-cinnamoyl-3'-methylureido)-4-hydroxybenzylcephalosporin

From D-α-(3'-cinnamoyl-3'-methylureido)-4-hydroxyphenylacetic acid and7-aminocephalosporanic acid by the method of example 21 in 35.9% yield;n.m.r. [(CD₃)₂ SO+D₂ O], δ=8.0-6.6 (11H,m, aromatic and olefinicprotons), 5.8-5.4 (2H,m, C₇ and α-protons), 5.1-4.7 (3H,m, C₆ and --CH₂OCO--), 3.35 (5H,s, >N--CH₃ and C₂ methylene), 2.05 (3H,s, --OCOCH₃);u.v. spectrum (95% ethanol), λ_(max) 225 (ε=24,468) and 282 nm(ε=19,152). Paper chromatography showed one zone, R_(f) =0.65.

EXAMPLE 22 Sodium7-[D-α-(3'-cinnamoyl-3'-methylureido)phenylacetamido]-3-(2"-methyl-1",3",4"-thiadiazol-5"-ylthio)methylceph-3-em-4-carboxylate

D-α-(3-Cinnamoyl-3-methylureido)phenylacetic acid (0.85 g., 0.0025 M) inanhydrous acetone (10 ml.) was cooled to <-10° then N-methylmorpholine(1 drop), triethylamine (0.35 ml.) and ethyl chloroformate (0.24 ml.)were added. The resulting suspension was stirred at <-10° for 15 minutesthen7-amino-3-(2'-methyl-1',3',4'-thiadiazol-5'-ylthio)methylceph-3-em-4-carboxylicacid (0.86 g., 0.0025 M) and triethylamine (0.35 ml.) in 50% aqueousacetone (15 ml.) pre-cooled to 0° were added. The solution was stirredat R.T. for two hours, the acetone was removed in vacuo, the residuediluted with water (50 ml.) and washed with ethyl acetate (2×50 ml.).The aqueous layer was covered with ethyl acetate (50 ml.) and acidifiedto pH 1.5 with 1 N hydrochloric acid then the ethyl acetate layer wasseparated and the aqueous extracted with ethyl acetate (50 ml.). Thecombined ethyl acetate solutions were washed with water (2×50 ml.) andbrine (50 ml.), dried over anhydrous magnesium sulphate and treated with2 N sodium 2-ethylhexoate in methyl isobutyl ketone (0.7 ml.). Theprecipitated sodium salt was collected, washed with anhydrous either anddried in vacuo. Yield 0.53 g., 30.9%; n.m.r. [(CD₃)₂ SO+D₂ O], δ=8.0-7.0(12H,m, aromatic and olefinic protons), 5.8-5.4 (2H,m, C₇ andα-protons), 5.1-4.8 (1H,m, C₆ proton), 4.8-4.0 (2H,m, --CH₂ --S--), 3.34(5H, singlet covering a multiplet, >N--CH₃ and C₂ methylene), 2.67(3H,s, thiadiazole methyl protons); u.v. spectrum [95% ethanol]λ_(max)219 (ε=24,010) and 282 nm (ε=27,901). Paper chromatography showed onezone, R_(f) =0.63.

EXAMPLE 23 Sodium7-[D-α-(3'-cinnamoyl-3'-methylureido)phenylacetamido]-3-(1"-methyl-1"H-tetrazol-5"-ylthio)methylceph-3-em-4-carboxylate

N-Methylmorpholine (1 drop), triethylamine (0.35 ml.) and ethylchloroformate (0.24 ml.) were added to D-α-(3-cinnamoyl-3-methylureido)phenylacetic acid (0.85 g., 0.0025 M) in anhydrous acetone (20 ml.) at<-10°, and stirred at that temperature for 15 minutes.7-Amino-3-(1'-methyl-1'H-tetrazol-5'-ylthio)methylceph-3-em-4-carboxylicacid (0.82 g., 0.0025 M) and triethylamine (0.35 ml.) in 50% aqueousacetone (30 ml.) cooled to 0°, was added and the solution stirred atR.T. for two hours. Acetone was removed in vacuo and the residue dilutedwith water (100 ml.), washed with ethyl acetate (2×50 ml.), covered withethyl acetate (50 ml.) and acidifed to pH 1.5 with 1 N hydrochloricacid. The layers were separated and the aqueous solution extracted withethyl acetate (50 ml.). The combined extracts were washed with water(2×50 ml.). then dried over anhydrous magnesium sulphate and teated with2 N sodium 2-ethylhexoate in methyl isobutyl ketone (0.8 ml.). Theprecipitated salt was collected, washed with anhydrous ether and driedin vacuo. Yield 0.64 g., 38.2%; n.m.r. [(CD₃)₂ SO+D₂ O]. δ=8.0-7.1(12H,m, aromatic and olefinic protons), 5.8-5.5 (2H,m, C₇ andα-protons), 5.1-4.8 (1H,m, C₆ proton), 4.6-4.1 (2H,m, --CH₂ --S--), 3.95(3H,s, tetrazole methyl protons), 3.33 (5H, singlet covering amultiplet, >N--CH₃ and C₂ methylene protons); u.v. spectrum (95%ethanol), λ_(max) 282 nm (ε=25,277). Paper chromatography showed onezone, R_(f) =0.66.

EXAMPLE 24 Sodium D-α-(3-benzoyl-3-methylureido)benzyl cephalosporin

Anhydrous triethylammonium D-α-aminobenzyl cephalosporin (0.005 M) indichloromethane (30 ml) [prepared from D-α-amino-benzyl cephalosporindihydrate (2.2 g) as in example 3] was cooled in an ice bath and thenN-chlorocarbonyl-N-methylbenzamide (0.98 g., 0.005 M) in dichloromethane(15 ml) was added. The solution was stirred at R.T. for two hours thenevaporated to dryness in vacuo. The residue was dissolved in water (100ml), washed with ethyl acetate (2×50 ml) and acidified to pH 1.5 with 1N hydrochloric acid in the presence of ethyl acetate (50 ml). Theorganic layer was separated off, the aqueous layer extracted with ethylacetate (50 ml) and the combined ethyl acetate extracts were washed withwater (2×100 ml) and saturated brine (50 ml) then dried over anhydrousmagnesium sulphate. The dried solution was treated with 2 N sodium2-ethylhexoate in methyl isobutyl ketone (1.5 ml), diluted withanhydrous ether (200 ml) and the precipitated sodium salt collected anddried in vacuo. Yield 1.68 g., 57.2%; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=7.7-7.2 (10H,m, aromatic protons), 5.8-5.4 (2H,m, C₇ and α-protons),5.2-4.6 (3H,m, C₆ proton and --CH₂ OCO--), 3.6-2.8 (2H,m, C₂ methyleneprotons), 3.08 (3H,s, >NCH₃), 2.00 (3H,s, --OCOCH₃) U.V. spectrum (95%EtOH), λ_(max) 263 nm (ε=8,710). Paper chromatography inn-butanol-ethanol-water showed one zone, R_(f) =0.52.

The following Examples 25-37 were prepared by the method described inexample 24.

EXAMPLE 25 Sodium D-α-(3-methyl-3-acetylureido)benzyl cephalosporin

From N-chlorocarbonyl-N-methylacetamide and D-α-aminobenzylcephalosporin dihydrate in 27.0% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂O], δ=7.43 (5H,s, aromatic protons), 6.8-6.5 (2H,m, C₇ and α-protons),5.2-4.6 (3H,m, C₆ proton nd --CH₂ OCO--), 3.7-2.7 (2H,m, C₂ methyleneprotons), 3.20 (3H,s, >NCH₃), 2.33 (3H,s, --COCH₃), 2.03 (3H,s,--OCOCH₃); U.V. spectrum (95% ethanol), λ_(max) 266 nm (ε=7,920). Paperchromatography showed one zone, R_(f) =0.42.

EXAMPLE 26 Sodium D-α-[3-(2-methylcrotonoyl)-3-methylureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-2-methylcrotonamide and D-α-aminobenzylcephalosporin dihydrate in 37.4% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂O], δ=1.5-2.2 (6H,m, ═CHCH₃ and --OCOCH₃), 3.12 (3H,s, >N--CH₃), 3.2-3.4(2H,m, C₂ methylene protons), 4.9 (3H,m, C₆ proton and --CH₂ OCO--), 5.6(2H,m, C₇ and α-protons), 7.4 (5H,m, aromatic protons); U.V. spectrum(95% ethanol), λ_(max) 257 nm (ε=7,930). Paper chromatography showed onezone, R_(f) =0.62

EXAMPLE 27 Sodium D-α-(3-phenylacetyl-3-methylureido)benzylcephalosporin

From N-chlorocarbonyl-N-methylphenylacetamide and D-α-aminobenzylcephalosporin dihydrate in 10.5% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂O], δ=2.03 (3H,s, --OCOCH₃), 3.29 (5H,singlet covering a multiplet >NCH₃and C₂ methylene protons), 4.04 (2H,s, --COCH₂ Ph), 4.92 (3H,m, --OCOCH₂-- and C₆ proton), 5.7 (2H,m, C₇ and α-protons), 7.32, 7.40 (10H,d,aromatic protons); U.V. spectrum (95% ethanol), λ_(max) 264 nm(ε=5,720). Paper chromatography showed a zone at R_(f) =0.51.

EXAMPLE 28 Sodium D-α-[3-(4-phenylbutanoyl)-3-methylureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-4-phenylbutyramide and D-α-aminobenzylcephalosporin dihydrate in 49.2% yield; N.M.R. spectrum [(CD₃)₂ S+D₂ O],δ=2.02 (7H, singlet covering a multiplet, --OCOCH₃ and --CH₂ CH₂ Ph),2.7 (2H,m, --COCH₂ --), 3.18 (5H, singlet coverings multiplet, >NCH₃ andC₂ methylene protons), 4.92 (3H,m, --CH₂ OCO-- and C₆ proton), 5.65(2H,m, C₇ and α-protons), 7.26 (5H,s, aromatic protons), 7.40 (5H,s,aromatic protons); U.V. spectrum (95% ethanol), λ_(max) 261 nm(ε=7,785). Paper chromatography showed a zone at R_(f) =0.62.

EXAMPLE 29 Sodium D-α-(3-oct-2'-enoyl-3-methylureido)benzylcephalosporin

From N-chlorocarbonyl-N-methyloct-2-enamide and D-α-aminobenzylcephalosporin dihydrate in 25% yield; N.M.R. spectrum, [(CD₃)₂ SO+D₂ O],δ=0.8-1.5 (9H,m, --(CH₂)₃ CH₃), 2.02 (5H, singlet covering a multiplet,--OCOCH₃ and --CH₂ CH═), 3.25 (5H, singlet covering a multiplet, >NCH₃and C₂ methylene protons), 4.8-5.0 (3H,m, C₆ proton and --CH₂ OCO--),5.5-5.7 (2H,m, C₇ and α-protons), 6.5-7.5 (2H,m, olefinic protons), 7.42(5H,s, aromatic protons). Paper chromatography showed a zone at R_(f)=0.58.

EXAMPLE 30 Sodium D-α-(3-furoyl-3-methylureido)benzyl cephalosporin

From N-chlorocarbonyl-N-methyl-2-furamide and D-α-aminobenzylcephalosporin dihydrate in 55.0% yield; N.M.R. spectrum [(CD₃)₂ S+D₂ O],δ=2.04 (3H,s, --OCOCH₃), 3.37 (5H, singlet covering a multiplet, >NCH₃and C₂ methylene protons), 4.8-5.0 (3H,m, --OCOCH₂ -- and C₆ proton),5.5-5.8 (2H,m, C₇ and α-protons), 6.6-8.0 (8H,m, aromatic and furylprotons); U.V. spectrum (95% ethanol), λ_(max) 268 nm (ε=19,990). Paperchromatography showed a zone at R_(f) =0.39.

EXAMPLE 31 Sodium D-α-(3-cinnamoyl-3-ethylureido)benzyl cephalosporin

From N-chlorocarbonyl-N-ethylcinnamamide and D-α-aminobenzylcephalosporin dihydrate in 27.4% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂O], δ=1.2-1.4 (3H,m, CH₃ CH₂ --), 2.04 (3H,s, --OCOCH₃), 3.2-3.5 (2H,m,C₂ methylene protons), 3.7-4.2 (2H,m, >N--CH₂ --), 4.9-5.05 (3H,m,--OCOCH₂ -- and C₆ proton), 5.6-5.8 (2H,m, C₇ and α-protons), 7.3-8.0(12H,m, aromatic and olefinic protons), U.V. spectrum (95% ethanol),λ_(max) 285 nm (ε=19.370). Paper chromatography showed a zone at R_(f)=0.57.

EXAMPLE 32 Sodium D-α-(3-acetylimidazolin-2-on-1-ylcarbonylamino)benzylcephalosporin

From D-α-aminobenzyl cephalosporin dihydrate and3-acetyl-1-chlorocarbonylimidazolidin-2-one in 61.9% yield; N.M.R.spectrum [(CD₃)₂ SO+D₂ O], δ=7.42 (5H,s, aromatic protons), 5.8-5.3(2H,m, C₇ and α-protons), 5.2-4.6 (3H,m, C₆ proton and --CH₂ OCO--),3.73 (4H,s, imidazolidone methylene protons), 3.6-2.9 (2H,m, C₂methylene protons), 2.42 (3H,s, >NCOCH₃), 1.99 (3H,s, --OCOCH₃); U.V.spectrum (95% ethanol), λ_(max) 260 nm (ε=8,180). Paper chromatographyshowed one zone R_(f) =0.30

EXAMPLE 33 SodiumD-α-(3-methylsulphonylimidazolidin-2-on-1-ylcarbonylamino)benzylcephalosporin

From D-α-aminobenzyl cephalosporin dihydrate and1-chlorocarbonyl-3-methylsulphonylimidazolin-2-one in 38.1% yield;N.M.R. spectrum [(CD₃)₂ S+D₂ O], δ=7.48 (5H,s, aromatic protons),5.7-5.4 (2H,m, C₇ and α-protons), 5.2-4.5 (3H,m, C₆ proton and --CH₂OCO--), 3.89 (4H,s, imidazolidinone methylene protons), 3.7-2.8 (2H,m,C₂ methylene protons), 3.38 (3H,s, --SO₂ CH₃), 2.03 (3H,s, --OCOCH₃);U.V. spectrum (95% ethanol), λ_(max) 262 nm (ε=7,825). Paperchromatography showed one zone, R_(f) =0.27.

EXAMPLE 34 Sodium D-α-(2,4,4-trimethylallaphanamido)benzyl cephalosporin

From 1-chlorocarbonyl-1,3,5-trimethylurea and D-α-aminobenzylcephalosporin dihydrate in 33.2% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂O], δ=2.02 (3H,s, --OCOCH₃), 2.88 [6H,s, --N(CH₃)₂ ], 3.0 (3H,s, >NCH₃),3.33 (2H,m, C₂ methylene protons), 4.93 (3H,m, C₆ proton and --CH₂OCO--), 5.58 (2H,m, C₇ and α-protons), 7.40 (5H,m, aromatic protons);U.V. spectrum (95% ethanol), λ_(max) 266 nm (ε=6,890). Papercharomatography showed a zone at R_(f) =0.30.

EXAMPLE 35 Sodium D-α-(3-phenoxyacetyl-3-methylureido)benzylcephalosporin

From N-chlorocarbonyl-N-methylphenoxyacetamide and D-α-aminobenzylcephalosporin dihydrate in 62.1% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂O], δ=2.01 (3H,s, --OCOCH₃), 3.23 (5H, m, >NCH₃ and C₂ methyleneprotons), 4.92 (3H,m, --CH₂ OCO-- and C₆ proton) 5.10 (2H,s, PhOCH₂ --),5.61 (2H,m, C₇ and α-protons), 6.9 to 7.5 (10H,m, aromatic protons);U.V. spectrum (95% ethanol), λ_(max) 266 nm (ε=9,000). Paperchromatography showed a zone at R_(f) =0.50

EXAMPLE 36 Sodium D-α-[3-(2-chlorobenzoyl)-3-methylureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-2-chlorobenzamide and D-α-aminobenzylcephalosporin dihydrate in 28.5% yield; N.M.R. spectrum [(CD₃)₂ SO═D₂O], δ=2.03 (3H,s, --OCOCH₃), 3.01 (3H,s, >N--CH₃), 3.2-3.5 (2H,m, C₂methylene protons), 4.8-5.1 (3H,m, --CH₂ OCO-- and C₆ protons), 5.6-5.8(2H,m, C₇ and α-protons), 7.3-7.7 (9H,m, aromatic protons); U.V.spectrum (95% ethanol), λ_(max) 266 nm (ε=7,920), Paper chromatographyshowed a zone at R_(f) =0.58.

EXAMPLE 37 Sodium D-α-[3-(2-methylbenzoyl)-3-methylureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-2-methylbenzamide and D-α-aminobenzylcephalosporin dihydrate in 51.5% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂O], δ=2.01 (3H,s, --OCOCH₃), 2.28 (3H,s, benzoyl --CH₃), 2.96 (3H,s,>N--CH₃), 3.2-3.4 (2H,m, C₂ methylene protons), 4.9-5.1 (3H,m, --CH₂OCO-- and C₆ proton), 5.6-5.8 (2H,m, C₇ and α-protons), 7.3-7.5 (9H,m,aromatic protons); U.V. spectrum (95% ethanol), λ_(max) 260 nm(ε=8,310). Paper chromatography showed a zone at R_(f) =0.50

EXAMPLE 38 Sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

7-(D-α-Aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid trifluoroacetic acid (t.f.a.) salt (1.77 g., 0.003 M) andtriethylamine (1.35 ml) in dichloromethane (30 ml) were cooled in an icebath and treated with N-chlorocarbonyl-N-methylcinnamamide (0.78 g.,0.0035 M) in dichloromethane (10 ml). The solution was stirred at R.T.for three hours then evaporated to dryness in vacuo, the residuedissolved in water (50 ml) and washed with ethyl acetate (2×50 ml). Theaqueous solution was covered with ethyl acetate (50 ml), acidified to pH1.5 with 1 N hydrochloric acid, filtered, the ethyl acetate collectedand the aqueous layer extracted with a further portion of ethyl acetate(50 ml). The combined extracts were washed with water (2×50 ml) andsaturated brine (25 ml), dried over anhydrous magnesium sulphate andtreated with 2 N sodium 2-ethylhexoate in methyl isobutyl ketone (1.0ml). Anhydrous ether (200 ml) was added and the precipitated sodium saltcollected and dried in vacuo. Yield 0.96 g., 46.6%; N.M.R. spectrum[(CD₃)₂ SO+D₂ O], δ=8.0-7.0 (12H,m, aromatic and olefinic protons),5.8-5.5 (2H,m, C₇ and α-protons), 4.93 [1H,d,(J=5Hz), C₆ -proton],4.7-4.1 (2H,m, --CH₂ S--), 3.8-2.9 (2H,m, C₂ methylene protons), 3.25(3H,s, >NCH₃), 2.67 (3H,s, thiadiazole --CH₃); U.V. spectrum (95%ethanol), λ_(max) 282 nm (ε=30,630). Paper chromatography showed onezone, R_(f) =0.65.

The following examples were prepared as described in example 38.

EXAMPLE 39 Sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From 7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylic acid t.f.a. salt andN-chlorocarbonyl-N-methyl-cinnamamide in 50.7% yield; N.M.R. spectrum[(CD₃)₂ SO+D₂ O] δ=7.9-7.1 (12H,m, aromatic and olefinic protons),5.8-5.5 (2H,m, C₇ and α-protons), 5.1-4.8 (1H,m, C₆ proton), 4.7-4.0(2H,m, --CH₂ S--), 3.93 (3H,s, tetrazole --CH₃), 3.8-3.1 (2H,m, C₂methylene protons), 3.33 (3H,s, >NCH₃); U.V. spectrum (95% ethanol),λ_(max) 282 nm (ε=24,490). Paper chromatography showed one zone, R_(f)=0.51.

EXAMPLE 40 Sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(1H-1,2,4-triazol-3-ylthio)methylceph-3-em-4-carboxylate

From7-(D-α-aminophenylacetamido)-3-(1H-1,2,4-triazol-3-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt and N-chlorocarbonyl-N-methylcinnamamide in 55.7%yield; N.M.R. [(CD₃)₂ SO+D₂ O], δ=8.0-7.0 (13H, aromatic, olefinic andtriazole protons), 5.7-5.4 (2H,m, C₇ and α-protons), 5.0-4.3 (3H,m, C₆proton and --CH₂ S--), 3.8-3.0 (2H,m, C₂ methylene protons), 3.33 (3H,s,>N--CH₃); U.V. spectrum (95% ethanol), λ_(max) 287 nm (ε=21,980). Paperchromatography showed a zone at R_(f) =0.58.

EXAMPLE 41 Sodium7-[D-α-(2,4-dimethylallophanamido)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt and 2,4-dimethylallophanoyl chloride in 58.7% yield;N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.7-7.1 (5H,m, aromatic protons),5.7-5.5 (2H,m, C₇ and α-protons), 5.0-4.8 (1H,m, C₆ proton), 4.7-4.1(2H,m, --CH₂ S--), 3.10 (3H,s, >NCH₃), 2.70 (6H,s, --NHCH₃ andthiadiazole --CH₃); U.V. spectrum (95% ethanol), λ_(max) 274 nm(ε=13,010). Paper chromatography showed one zone R_(f) =0.41.

EXAMPLE 42 Sodium7-[D-α-(2,4-dimethylallophanamido)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt and 2,4-dimethylallophanoyl chloride in 53.0% yield;N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.42 (5H,s, aromatic protons),5.7-5.5 (2H,m, C₇ and α-protons), 4.88 [1H,d, (J=5 Hz), C₆ proton],4.6-4.0 (2H,m, --CH₂ S--), 3.93 (3H,s, tetrazole --CH₃), 3.8-3.1 (2H,m,C₂ methylene protons), 3.10 (3H,s, >N--CH₃), 2.70 (3H,s, --NHCH₃); U.V.spectrum (95% ethanol), λ_(max) 268 nm (ε=8,020). Paper chromatographyshowed one zone R_(f) =0.47.

EXAMPLE 43 Sodium7-[D-α-(3-acetyl-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt and N-chlorocarbonyl-N-methylacetamide in 76.9% yield;N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.47 (5H,s, aromatic protons),5.8-5.4 (2H,m, C₇ and α-protons), 4.93 [1H,d, (J=5 Hz), C₆ proton],4.7-4.0 (2H,m, --CH₂ S--), 3.8-3.0 (2H,m, C₂ methylene protons), 3.21(3H,s, >N--CH₃), 2.72 (3H,s, thiadiazole --CH₃), 2.33 (3H,s, --COCH₃);U.V. spectrum (95% ethanol), λ_(max) 275 nm (ε=12,410). Paperchromatography showed one zone, R_(f) =0.31.

EXAMPLE 44 Sodium7-[D-α-(3-acetyl-3-methylureido)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt and N-chlorocarbonyl-N-methylacetamide in 24.8% yield;N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.40 (5H,s, aromatic protons),5.7-5.4 (2H,m, C₇ and α-protons), 4.89 [1H,d, (J=5 Hz), C₆ proton],4.6-4.0 (2H,m, --CH₂ S--), 3.94 (3H,s, tetrazole --CH₃), 3.8-3.1 (2H,m,C₂ methylene protons), 3.18 (3H,s,>N--CH₃), 2.30 (3H,s, --COCH₃); U.V.spectrum (95% ethanol), λ_(max) 265 nm (ε=8,040). Paper chromatographyshowed one zone R_(f) =0.33.

EXAMPLE 45 Sodium7-[D-α-[3-(4-phenylbutanoyl)-3-methylureido]phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-4-phenylbutyramide and 7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 46.8% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.8-2.2 (2H,m, PhCH₂ CH₂ CH₂ --), 2.5-2.9 (7H,m, thiadiazole --CH₃,--COCH₂ CH₂ CH₂ Ph), 3.17 (3H,s, >N--CH₃), 3.3-3.5 (2H,m, C₂ methyleneprotons), 4.2-4.7 (2H,m, --CH₂ S--), 4.8-5.0 (1H,m, C₆ proton), 4.5-4.8(2H,m, C₇ and α-protons), 7.27 (5H,s, aromatic protons), 7.41 (5H,s,aromatic protons); U.V. spectrum (95% ethanol), λ_(max) 275 nm(ε=12,770). Paper chromatography showed a zone at R_(f) =0.62.

EXAMPLE 46 Sodium 7-[D-α-[3-(4-phenylbutanoyl)-3-methylureido]phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-4-phenylbutyramide and7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 17.5% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.7-2.2 (2H,m,PhCH₂ CH₂ CH₂ --), 2.5-2.7 (4H,m, PhCH₂ CH₂ CH₂ CO),3.16 (3H,s, >N--CH₃), 3.4-3.6 (2H,m, C₂ methylene protons), 3.94 (3H,s,tetrazole --CH₃), 4.3-4.5 (2H,m, --CH₂ --S--), 4.8-5.0 (1H,m, C₆proton), 5.5-5.8 (2H,m, C₇ and α-protons), 7.25 (5H,s, aromaticprotons), 7.37 (5H,s, aromatic protons); U.V. spectrum (95% ethanol),λ_(max) 270 nm (ε=8,410). Paper chromatography showed a zone at R_(f)=0.47.

EXAMPLE 47 Sodium7-[D-α-[3-(2-methylcrotonoyl)-3-methylureido]phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-2-methyl crotonamide and7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 17.1% yield, N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.6-1.9 (6H,m, 2×crotonoyl --CH₃), 3.11 (3H,s, >N--CH₃), 3.4-3.6(2H,m, C₂ methylene protons), 4.96 (3H,s, tetrazole --CH₃), 4.2-4.4(2H,m, --CH₂ S--), 4.7-5.1 (1H,m, C₆ proton), 5.5-6.0 (3H,m, --CH═C>, C₇and α-protons), 7.40 (5H,s, aromatic protons), U.V. spectrum (95%ethanol), λ_(max) 270 nm (ε=9,260). Paper chromatography showed a zoneat R_(f) =0.43.

EXAMPLE 48 Sodium7-[D-α-[3-(2-methylcrotonoyl)-3-methylureido]phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-2-methyl crotonamide and7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 35.6% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.6-1.9 (6H,m, 2×crotonoyl --CH₃), 2.69 (3H,s, thiadiazole --CH₃),3.12 (3H,s, >N--CH₃), 3.4-3.6 (2H,m, C₂ methylene protons), 4.3-4.6(2H,m, --CH₂ S--), 4.9-5.1 (1H,m, C₆ proton), 5.5-6.0 (3H,m, --CH═C>, C₇and α-protons), 7.41 (5H,s, aromatic protons); U.V. spectrum (95%ethanol), λ_(max) 275 nm (ε=13,470). Paper chromatography showed a zoneat R_(f) =0.52.

EXAMPLE 49 Sodium7-[D-α-[3-(3-phenylpropionyl)-3-methylureido]phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-3-phenylpropionamide and7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methyl-ceph-3-em-4-carboxylicacid t.f.a. salt in 34.9% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=2.68 (3H,s, thiadiazole --CH₃), 2.94 (4H,s, --CH₂ CH₂ Ph), 3.19 (3H,s,>N--CH₃), 3.3-3.5 (2H,m, C₂ methylene protons), 4.2-4.5 (2H,m, --CH₂S--), 4.8-5.0 (1H,m,C₆ proton), 5.4-5.7 (2H,m, C₇ and α-protons), 7.28(5H,s, aromatic protons), 7.37 (5H,s, aromatic protons); U.V. spectrum(95% ethanol), λ_(max) 275 nm (ε=13,500). Paper chromatography showed azone at R_(f) =0.61.

EXAMPLE 50 Sodium7-[D-α-[3-(3-phenylpropionyl)-3-methylureido]phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-3-phenylpropionamide and (7-D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methyl-ceph-3-em-4-carboxylicacid in t.f.a. salt 26.8% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=2.94 (4H,s, --CH₂ CH₂ Ph), 3.19 (3H,s, >N--CH₃), 3.-3.8 (2H,m, C₂methylene protons), 3.95 (3H,s, tetrazole --CH₃), 4.2-4.5 (2H, --CH₂S--), 4.8-5.0 (1H,m, C₆ proton), 5.5-5.8 (2H,m, C₇ and α-protons),7.2-7.5 (10H,d, aromatic protons); U.V. spectrum (95% ethanol), λ_(max)260 nm (ε=9,120). Paper chromatography showed a zone at R_(f) =0.54.

EXAMPLE 51 Sodium7-[D-α-[3-(3-methylcrotonoyl)-3-methylureido]phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-3-methylcrotonamide and7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 24.6% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.9-2.1 (6H,m, --CH═C(CH₃)₂), 2.70 (thiadiazole --CH₃), 3.18 (3H,s,>N--CH₃), 3.3-3.6 (2H,m, C₂ methylene protons), 4.3-4.5 (2H,m, --CH₂S--), 4.8-5.0 (1H,m, C₆ proton), 5.5-5.7 (2H,m, C₇ and α-protons),6.1-6.3 (1H,m, --CH═C<), 7.41 (5H,s, aromatic protons); U.V. spectrum(95% ethanol), λ_(max) 270 nm (ε=11,870). Paper chromatography showed azone at R_(f) =0.56.

EXAMPLE 52 Sodium7-[D-α-[3-(3-methylcrotonoyl)-3-methylureido]phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-3-methylcrotonamide and7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 56.7% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.9-2.1 (6H,m, --CH═C(CH₃)₂), 3.18 (3H,s, >N--CH₃), 3.4-3.6 (2H,m, C₂methylene protons), 3.96 (3H,s, tetrazole --CH₃), 4.3-4.5 (2H,m, --CH₂S--), 4.9-5.0 (1H,m, C₆ proton), 5.5-5.8 (2H,m, C₇ and α-protons),6.1-6.3 (1H,m, --CH═C<), 7.40 (5H,s, aromatic protons); U.V. spectrum(95% ethanol), λ_(max) 274 nm (ε=10,130). Paper chromatography showed azone at R_(f) =0.40.

EXAMPLE 53 Sodium7-[D-α-(3-furoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methylfuramide and7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 32.6% yield, N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=2.69 (3H,s, thiadiazole --CH₃), 3.35 (5H,singlet covering multiplet,>N--CH₃ and C₂ methylene protons), 4.2-4.5 (2H,m, --CH₂ S--), 4.9-5.1(1H,m, C₆ proton), 5.5-5.8 (2H,m, C₇ and α-protons), 6.6-8.0 (8H,m,aromatic and furyl protons); U.V. spectrum (95% ethanol), λ_(max) 272 nm(ε=25,690). Paper chromatography showed a zone at R_(f) =0.50.

EXAMPLE 54 Sodium7-[D-α-(3-crotonoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl crotonamide and7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 38.8% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.8-2.1 (3H,m, crotonyl --CH₃), 2.70 (3H,s, thiadiazole --CH₃), 3.25(3H,s, >N--CH₃), 3.5-3.7 (2H,m, C₂ methylene protons), 4.3-4.5 (2H,m,--CH₂ S--), 4.9-5.1 (1H,m, C₆ proton), 5.5-5.8 (2H,m, C₇ and α-protons),6.6-7.1 (2H,m, olefinic protons), 7.40 (5H,s, aromatic protons); U.V.spectrum (95% ethanol), λ_(max) 273 nm (ε=14,510), Paper chromatographyshowed a zone at R_(f) =0.65.

EXAMPLE 55 Sodium7-[D-α-(3-crotonoyl-3-methylureido)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methylcrotonamide and7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 30.6% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=1.9-2.1 (3H,m, crotonyl --CH₃), 3.23 (3H,s, >N--CH₃), 3.4-3.7 (2H,m,C₂ methylene protons), 3.94 (3H,s, tetrazole --CH₃), 4.2-4.4 (2H,m,--CH₂ S--), 4.9-5.1 (1H,m, C₆ proton), 5.5-5.8 (2H,m, C₇ and α-protons),6.6-7.1 (2H,m, olefinic protons), 7.39 (5H,s, aromatic protons); U.V.spectrum (95% ethanol), λ_(max) 270 nm (ε=10,010). Paper chromatographyshowed a zone at R_(f) =0.45.

EXAMPLE 56 Sodium7-[D-α-[3-(2-chlorobenzoyl)-3-methylureido]phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-2-chlorobenzamide and7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 31.8% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=2.68 (3H,s, thiadiazole --CH₃), 2.98 (3H,s, >N--CH₃), 3.3-3.6 (2H,m,C₂ methylene protons), 4.3-4.6 (2H,m, --CH₂ S--), 4.8-5.0 (1H,m, C₆proton), 5.5-5.8 (2H,m, C₇ and α-protons), 7.3-7.7 (9H,d, aromaticprotons); U.V. spectrum (95% ethanol), λ_(max) 276 nm (ε=11,910). Paperchromatography showed a zone at R_(f) =0.54.

EXAMPLE 57 Sodium7-[D-α-[3-(2-methylbenzoyl)-3-methylureido]phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From N-chlorocarbonyl-N-methyl-2-methylbenzamide and7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt in 32.7% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O],δ=2.27 (3H,s, benzoyl --CH₃), 2.68 (3H,s, thiadiazole --CH₃), 2.97(3H,s, >N--CH₃), 3.3-3.6 (2H,m, C₂ methylene protons), 4.4-4.6 (2H,m,--CH₂ S--), 5.3-5.5 (1H,m, C₆ proton), 5.6-5.8 (2H,m, C₇ and α-protons),7.3-7.6 (9H,m, aromatic protons); U.V. spectrum (95% ethanol), λ_(max)274 nm (ε=12,190). Paper chromatography showed a zone at R_(f) =0.62.

EXAMPLE 58 Sodium7-[D-α-(3-acetylimidazolidin-2-on-1-ylcarbonylamino)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

From7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid t.f.a. salt and 3-acetyl-1-chlorocarbonylimidazolidin-2-one in74.3% yield; N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.43 (5H,s, aromaticprotons), 5.7-5.4 (2H,m, C₇ and α-protons), 5.1-4.8 (1H,m, C₆ proton),4.7-4.1 (2H,m, --CH₂ S--), 3.70 (4H,s, imidazolidinone methyleneprotons), 3.8-3.0 (2H,m, C₂ methylene protons), 2.70 (3H,s, thiadiazole--CH₃), 2.45 (3H,s, >NCOCH₃); U.V. spectrum (95% ethanol), λ_(max) 274.5nm (ε=10,270). Paper chromatography showed one zone, R_(f) =0.43.

EXAMPLE 59 Sodium7-[D-α-(3-acetylimidazolidin-2-on-1-ylcarbonylamino)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

From 7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylic acid t.f.a. salt and3-acetyl-1-chlorocarbonylimidazolidin-2-one in 43.5% yield; N.M.R.spectrum [(CD₃)₂ SO+D₂ O], δ=7.47 (5H,s, aromatic protons), 5.8-5.4(2H,m, C₇ and α-protons), 5.0-4.8 (1H,m, C₆ proton), 4.7-4.0 (2H,m,--CH₂ S--), 3.96 (3H,s, tetrazole --CH₃), 3.70 (4H,s, imidazolidinonemethylene protons), 3.8-3.1 (2H,m, C₂ methylene protons), 2.45 (3H,s,>NCOCH₃); U.V. spectrum (95% ethanol), λ_(max) 265 nm (ε=8,400). Paperchromatography showed one zone, R_(f) =0.38.

EXAMPLE 60 Sodium D-α-(imidazolidin-2-on-1-ylcarbonylamino)benzylcephalosporin

Anhydrous triethylammonium D-α-aminobenzyl cephalosporin indichloromethane (30 ml) (prepared from the dihydrate (2.2 g., 0.005 M)as described in example 3) was cooled in an ice bath and1-chlorocarbonylimidazolidin-2-one (0.75 g., 0.005 M) in dichloromethane(10 ml) was added. The solution was stirred at R.T. for three hours thenevaporate to dryness in vacuo, the residue dissolved in water (100 ml)and washed with ethyl acetate (2×50 ml). The aqueous solution wascovered with ethyl acetate (50 ml) and acidified to pH 1.5 with 1 Nhydrochloric acid. The cephalosporin free acid, which precipitated, wascollected, washed with water (100 ml) and dried in vacuo. The free acidwas suspended in water (25 ml) and adjusted to pH 6.5 with 5 N sodiumhydroxide solution then filtered and freeze dried to give the sodiumsalt. Yield 1.77 g., 68.4%; N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.43(5H,s, aromatic protons), 5.8-5.4 (2H,m, C₇ and α-protons), 5.2-4.6(3H,m, C₆ proton and --CH₂ OCO--), 4.0-3.0 (6H,m, C₂ and imidazolidinonemethylene protons), 2.00 (3H,s, --OCOCH₃); U.V. spectrum (95% ethanol),λ_(max) 264 nm (ε=6,950). Paper chromatography showed one zone, R_(f)=0.27.

EXAMPLE 61 Sodium7-[D-α-(imidazolidin-2-on-1-ylcarbonylamino)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

Prepared from7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylicacid and 1-chlorocarbonylimidazolidin-2-one in 63.5% yield by the methoddescribed in Example 60. N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.43 (5H,s,aromatic protons), 5.8-5.4 (2H,m, C₇ and α-protons), 4.88 [1H,d, (J=5Hz), C₆ proton], 4.8-4.1 (2H,m, --CH₂ S--), 4.0-3.0 (6H,m, C₂ andimidazolidinone methylene protons), 2.69 (3H,s, thiadiazole --CH₃); U.V.spectrum (95% ethanol), λ_(max) 275 nm (ε=12,210). Paper chromatographyshowed one zone, R_(f) =0.38.

EXAMPLE 62 Sodium7-[D-α-(imidazolidin-2-on-ylcarbonylamino)phenylacetamido]-3-(1-methyl-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

7-(D-α-aminophenylacetamido)-3-(1-methyltetrazol-5-ylthio)methylceph-3-em-4-carboxylicacid (1.72., 0.003 M) was acylated with1-chlorocarbonylimidazolidin-2-one, as in example 60 to give the freeacid as a gummy solid. This was dissolved in acetone (30 ml), dried overanhydrous magnesium sulphate and treated with 2 N sodium 2-ethylhexoatein methyl isobutyl ketone. The precipitated sodium salt was collected,washed with anhydrous ether and dried in vacuo. Yield 1.16 g., 65.0%;N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=7.43 (5H,s, aromatic protons),5.8-5.4 (2H,m, C₇ and α-protons), 4.88 [1H,d, (J=5 Hz), C₆ proton],4.7-4.0 (2H,m, --CH₂ S--), 3.95 (3H,s, tetrazole --CH₃), 4.0-3.0 (6H,m,C₂ and imidazolidinone methylene protons); U.V. spectrum (95% ethanol),λ_(max) 271 nm (ε=8,600 ). Paper chromatography showed one zone, R_(f)=0.24.

EXAMPLE 63 Sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate

D-α-(3-Cinnamoyl-3-methylureido)benzyl cephalosporin (1.18 g., 0.002 M)and 2-methyl-5-mercapto-1,3,4-thiadiazole (0.53 g., 0.004 M) weredissolved in d.m.f. (25 ml) and pH 6.5 phosphate buffer solution (25ml), adjusted to pH 6.5 with solid sodium bicarbonate and then heated at60° for ten hours. The cooled solution was washed with ethyl acetate(2×100 ml) and acidified to pH 1.5 with 1 N hydrochloric acid in thepresence of ethyl acetate (50 ml). The organic phase was separated, theaqueous layer was extracted with more ethyl acetate (50 ml) then thecombined ethyl acetate extracts were washed with water (2×100 ml) andsaturated brine (50 ml), dried over anhydrous magnesium sulphate,treated with 2 N sodium 2-ethylhexoate in methyl isobutyl ketone (0.5ml) and diluted with anhydrous ether (200 ml). The precipitated sodiumsalt was washed with anhydrous ether and dried in vacuo. Yield 0.83 g.,60.5%. N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=8.0-7.0 (12H,m, aromatic andolefinic protons), 5.9-5.4 (2H,m, C₇ and α-protons), 4.89 [1H,d, (J=5Hz), C₆ proton], 4.8-4.0 (2H,m, --CH₂ S--), 3.9-3.0 (2H,m, C₂ methyleneprotons), 3.36 (3H,s,>N--CH₃), 2.70 (3H, s, thiadiazole --CH₃); U.V.spectrum (95% ethanol), λ_(max) 282 nm (ε=27,470). Paper chromatographyshowed one zone, R_(f) =0.66.

EXAMPLE 64 Sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-oxadiazol-5-ylthio)methylceph-3-em-4-carboxylate

Prepared by the method described in example 65 fromD-α-(3-cinnamoyl-3-methylureido)-benzyl cephalosporin and2-methyl-5-mercapto-1,3,4-oxadiazole in 55.2% yield; N.M.R. spectrum[(CD₃)₂ SO+D₂ O], δ=8.0-7.0 (12H,m, aromatic and olefinic protons),5.8-5.4 (2H,m, C₇ and α-protons), 4.88 [1H,d, (J=5 Hz), C₆ proton],4.6-3.9 (2H,m, --CH₂ S--], 3.8-2.8 (2H,m, C₂ methylene protons), 3.33(3H,s,>N--CH₃), 2.48 (3H,s, oxadiazole --CH₃); U.V. spectrum (95%ethanol), λ_(max) 280 nm (ε=24,800). Paper chromatography showed onezone R_(f) =0.59.

EXAMPLE 65 Sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

Prepared by the method described in example 63 fromD-α-(3-cinnamoyl-3-methylureido)benzyl cephalosporin and5-mercapto-1-methyl-1H-tetrazole in 56.7% yield; N.M.R. spectrum [(CD₃)₂SO+D₂ O], δ=8.0-7.0 (12H,m, aromatic protons), 5.8-5.5 (2H,m, C₇ andα-protons), 4.92 [1H,d, (J=5 Hz), C₆ proton], 4.7-4.0 (2H,m, --CH₂ S--),3.97 (3H,s, tetrazole --CH₃), 3.8-3.0 (2H,m, C₂ methylene protons), 3.34(3H,s,>N--CH₃); U.V. spectrum (95% ethanol), λ_(max) 284 nm (ε=25,075).Paper chromatography showed one zone, R_(f) =0.53.

EXAMPLE 66 Sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(benzoxazol-2-ylthio)methylceph-3-em-4-carboxylate

D-α-(3-Cinnamoyl-3-methylureido)benzyl cephalosporin and (1.18 g., 0.002M) 2-mercaptobenzoxazole (0.60 g., 0.002 M) in formamide (20 ml) andwater (25 ml) were adjusted to pH 7.0 with solid sodium bicarbonate thenheated at 60° for ten hours. The cooled solution was washed with ethylacetate (2×100 ml) filtered, covered with ethyl acetate (100 ml) andacidified to pH 1.5 with 1 N hydrochloric acid. The ethyl acetate wasseparated, the aqueous layer extracted with ethyl acetate (100 ml) andthe organic extracts combined, washed with water (2×100 ml) and brine(50 ml) then dried over anhydrous magnesium sulphate, treated with 2 Nsodium 2-ethylhexoate in methyl isobutyl ketone (0.7 ml) and dilutedwith ether (200 ml). The precipitated sodium salt was collected, washedwith ether, dried in vacuo, dissolved in water (50 ml), acidified to pH1.5 with 1 N hydrochloric acid and the precipitated free acid collected.This was dissolved in ethyl acetate (25 ml), filtered, diluted withether (25 ml), filtered then evaporated to dryness in vacuo and theresidue triturated with ether to give an off white solid (0.21 g.,),which was dissolved in acetone (3 ml), treated with 2 N sodium2-ethylhexoate in methyl isobutyl ketone (0.31 ml) and diluted withether (25 ml) to precipitate the sodium salt. This was collected anddried in vacuo 0.16 g., 12 % yield; N.M.R. [(CD₃)₂ SO+D₂ O], δ=8.0-6.9(16H,m, aromatic and olefinic protons), 5.8-5.5 (2H,m, C₇ andα-protons), 5.0-4.8 (1H,m, C₆ proton), 4.8-4.0 (2H,m, --CH₂ S--),3.8-3.0 (2H,m, C₂ methylene protons). 3.34 (3H,m,>N--CH₃), U.V. spectrum(95% ethanol), λ_(max) 290 nm (ε=33,050). Paper chromatography showed azone at R_(f) =0.80.

EXAMPLE 67 Disodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(4-sulphophenylthio)methylceph-3-em-4-carboxylate

D-α-(3-Cinnamoyl-3-methylureido)benzyl cephalosporin (1.18 g., 0.002 M)and 4-mercaptobenzenesulphonic acid (0.42 g., 0.002 M) in water (10 ml)and d.m.f. (15 ml) were adjusted to pH 6.5 with solid sodium bicarbonateand heated at 60° for eight hours. The solution was evaporated todryness in vacuo at R.T. and the residue was dissolved in water (100ml), acidified to pH 1.5 with `Amberlite` resin 1R-120(H), washed withethyl acetate (2×50 ml) and extracted with n-butanol (2×50 ml). Thebutanol was removed in vacuo to leave a solid which was triturated withether and collected, 0.83 g; N.M.R. spectrum [(CD₃)₂ SO+D₂ O], δ=8.0-7.0(16H,m, aromatic and olefinic protons), 5.9-5.5 (2H,m, C₇ andα-protons), 5.2-4.9 (1H,m, C₆ proton), 4.8-4.0 (2H,m, --CH₂ S--),3.9-3.0 (2H,m, C₂ methylene protons), 3.33 (3H,m,>N--CH₃). The solid wasdissolved in water, adjusted to pH 6.5 with 1 N sodium hydroxidesolution, washed with n-butanol and freeze dried to give the disodiumsalt, 0.66., 41.8% yield; U.V. spectrum (H₂ O), λ_(max) 275 nm(ε=8,040). Paper chromatography showed a zone at R_(f) =0.35.

EXAMPLE 68 Disodium7-[D-α-(3-Cinnamoyl-3-methylureido)phenylacetamido]-3-sulphomethylceph-3-em-4-carboxylate

Sodium D-α-(3-Cinnamoyl-3-methylureido)benzyl cephalosporin (0.05 g.,0.8 m. mole) was dissolved in warm formamide (8 ml). Sodium sulphite(0.15 g., 1.2 m.moles) in water (12 ml) was added, and sufficient SO₂gas passed in to give pH 7.0. The mixture was heated at 60° for 5 hours.If necessary, the pH was adjusted during this period by the addition ofSO₂ or 5 N sodium hydroxide solution. The mixture was diluted with waterand ice (total 30 ml) and acidified to pH 1.5 with strong acid ionexchange resin `Amberlite` IR-120(H). The solution was filtered,extracted with ethyl acetate (2×50 ml) and then with n-butanol (2×30ml). The butanol layers were combined, washed with a little water, thenwater (30 ml) was added, and the pH adjusted to 7.0 by the cautionsaddition of 1 N sodium hydroxide solution. The aqueous solution wasevaporated as far as possible under reduced pressure, and the residuedistilled under high vacuum at 40°. The residual gum was triturated withacetonitrile (5.0 ml), and the solid collected, dissolved in water (10ml) and n-butanol (20 ml). IR-120 (H) resin was added to pH 1.5, thebutanol layer separated, evaporated almost to dryness, reevaporated witha further 2×20 ml portions of n-butanol. The residue was partitionedbetween water (10 ml) and n-butanol (10 ml), 1.0 N sodium hydroxidesolution added to pH 7.0. The aqueous layer was freeze-dried, to 0.20g., N.M.R, spectrum (D₂ O) δ=7.2-7.6 (12H,m, aromatic and olefinicprotons), 3.25 (3H,s,>N--CH₃); U.V. spectrum (H₂ O), λ_(max) 265 nm(ε=6,990). Paper chromatography showed one zone at R_(f) =0.10.

EXAMPLE 69 Sodium D,L-α-(3-cinnamoyl-3-methylureido)thien-2-ylmethylcephalosporin

D,L-α-(3-Cinnamoyl-3-methylureido)thien-2-ylacetic acid (1.72 g., 0.005M), N-methylmorpholine (1 drop) and triethylamine (0.71 ml., 0.005 M) inanhydrous acetone (15 ml) were cooled to -10° and treated with ethylchloroformate (0.48 ml, 0.005 M). The solution was stirred at between-5° and 10° for 20 minutes then a solution of 7-aminocephalosporanicacid (1.36 g., 0.005 M) and triethylamine (0.71 ml) in 50% aqueousacetone (30 ml) cooled to 0° was added. The mixture was stirred at R.T.for two hours, the acetone was removed in vacuo, water (50 ml) added andwashed with ethyl acetate (2×50 ml). The aqueous solution was acidifiedto pH 1.5 with 1 N hydrochloric acid in the presence of ethyl acetate(50 ml) and extracted with a further portion of ethyl acetate (50 ml).The extracts were washed with water (2×100 ml) and brine (50 ml) thendried over anhydrous magnesium sulphate, treated with 2 N sodium2-ethylhexoate in methyl isobutyl ketone (1.8 ml) and diluted withanhydrous ether (200 ml). The precipitated sodium salt was collected,washed with ether and dried. Yield 1.12 g., 36.1%; N.M.R. spectrum[(CD₃)₂ SO+D₂ O], δ=8.0-6.7 (10H,m, aromatic, olefinic and thienylprotons), 6.0-5.8 (1H,m, α-proton), 5.7-5.3 (1H,m, C₇ proton), 5.2-4.5(3H,m, C₆ proton and --CH₂ OCO--), 3.8-3.0 (2H,m, C₂ methylene protons),3.33 (3H,s, >N--CH₃), 2.01 (3H,m, --OCOCH₃); U.V. spectrum (95%ethanol), λ_(max) 286 nm (ε=21,650). Paper chromatography showed onezone, R_(f) =0.53.

EXAMPLE 70 Sodium7-[D,L-α-(3-cinnamoyl-3-methylureido)thien-2-ylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate

Prepared from7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)-methylceph-3-em-4-carboxylicacid and D,L-α-(3-cinnamoyl-3-methylureido)thien-2-ylacetic acid by themethod described in example 69 in 34.0% yield; N.M.R. spectrum [(CD₃)₂SO+D₂ O], δ=8.0-6.8 (10H,m, aromatic, olefinic and thienyl protons),6.0-5.7 (1H,m, α-proton), 5.7-5.3 (1H,m, C₇ proton), 5.1-4.8 (1H,m, C₆proton), 4.6-4.0 (2H,m, --CH₂ S--), 2.93 (3H,s,tetrazole --CH₃), 3.8-3.1(2H,m, C₂ methylene protons), 3.34 (3H,s,>N--CH₃); U.V. spectrum (95%ethanol), λ_(max) 285 nm (ε=25,190). Paper chromatography showed onezone, R_(f) =0.52.

EXAMPLE 71 Sodium D-α-(3-cinnamoyl-3-methylureido)benzyl cephalosporin

D-α-(3-Cinnamoyl-3-methylureido)phenylacetic acid (1.69 g., 0.005 M) and1-hydroxybenztriazole monohydrate (0.77 g., 0.005 M) in t.h.f. (10 ml)were cooled in an ice bath then treated with dicyclohexylcarbodiimide(13 g., 0.005 M). The mixture was left at 5° overnight, then acetic acid(4 drops) was added, the mixture stirred at R.T. for 15 minutes afterwhich time the dicyclohexylurea was filtered off and washed withtetrahydrofuran (5 ml). The filtrate was added to 7-aminocephalosporanicacid (1.36 g., 0.005 M) in 50% aqueous t.h.f. (30 ml) which had beenadjusted to pH 6.5 with N-methylmorpholine. The solution was stirred atpH 6.5-7.0 for three hours then the t.h.f. was removed in vacuo and theresidue diluted with water (50 ml). This aqueous solution was worked upto give the sodium salt as described in example 71. Yield 1.21 g.,39.4%; N.M.R. [(CD₃)₂ SO+D.sub. 2 O], δ=8.0-7.0 (12H,m, aromatic andolefinic protons), 5.8-5.5 (2H,m, C₇ and α-protons), 5.2-4.6 (3H,m, C₆proton and --CH₂ OCO--), 3.8-2.9 (2H,m, C₂ methylene protons), 3.33(3H,s,>N--CH₃), 2.02 (3H,s, --OCOCH₃); U.V. spectrum (95% ethanol),λ_(max) 286 nm (ε=21,010). Paper chromatography showed one zone R_(f)=0.54.

We claim:
 1. A compound of the formula: ##STR11## wherein R is hydrogenor sodium.
 2. A compound of the formula: ##STR12## wherein R is##STR13## or CH₃ SO₂ -- and R₁ is hydrogen or sodium.
 3. The compound ofthe formula ##STR14## wherein a and a' are independently hydrogen,halogen or nitro;R₁ is phenyl, monohydroxyphenyl, mono- or dihalophenyl,monohydroxy substituted mono- or dihalophenyl or thienyl; R₂ is##STR15## wherein Z is methyl; R₃ is hydrogen, phthalidyl or anacyloxymethyl group of the formula ##STR16## wherein Y is C₁ -C₄ alkyl;and when R₃ is hydrogen, the pharmaceutically acceptable, nontoxic saltsthereof.
 4. The compound of claim 3 wherein R₁ is phenyl,monohydroxphenyl, monohydroxy substituted mono- or dihalophenyl orthienyl; R₃ is hydrogen or the pharmaceutically acceptable, nontoxicsalts thereof.
 5. The compound of claim 3, said compound being7-[α-(3-cinnamoyl-3-methyl-1-ureido)-2-phenylacetamido]-3-(1-methyl-1H-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylicacid.
 6. The compound sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4-carboxylate.7. The compound sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate.8. The compound sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(1H-1,2,4-triazol-3-ylthio)methylceph-3-em-4-carboxylate.9. The compound sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(2-methyl-1,3,4-oxadiazol-5-ylthio)methylceph-3-em-4-carboxylate.10. The compound sodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(benzoxazol-2-ylthio)methylceph-3-em-4-carboxylate.11. The compound disodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(4-sulphophenylthio)methylceph-3-em-4-carboxylate.12. The compound disodium7-[D-α-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-sulphomethylceph-3-em-4-carboxylate.13. The compound sodium7-[D,L-α-(3-cinnamoyl-3-methylureido)thien-2-ylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-carboxylate.